DOCSLIB.ORG

Lefamulin … [email protected] Paukner, Susanne 1; Flamm, Robert K

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Lefamulin … Susanne.Paukner@Nabriva.Com Paukner, Susanne 1; Flamm, Robert K In Vitro Activity of Lefamulin against S. aureus Collected Worldwide from Hospitalized Patients with Bacterial Pneumonia Nabriva Therapeutics 1218 www.nabriva.com Lefamulin … [email protected] Paukner, Susanne 1; Flamm, Robert K. 2; Schuchert, Jason 2; Gelone, Steven P. 3; Sader, Helio S. 2 1 Nabriva Therapeutics, Vienna, Austria; 2 JMI Laboratories, North Liberty, IA, USA; 3 Nabriva Therapeutics, King of Prussia, PA, USA ABSTRACT RESULTS Background: S. aureus (SA) is a well-recognized cause of pneumonia from both the community and hospital A . Lefamulin showed potent antibacterial activity against S. aureus isolates, including resistant isolates 1 S. aureus n settings. The clinical management of SA pneumonia is complicated by the invasive infection it can cause and , Total ( =1,273) (Figure 2, Tables 1 and 2). the high prevalence of methicillin resistance (MR).2 Lefamulin (LEF) is the first semi-synthetic pleuromutilin 1000 Lefamulin . Lefamulin was the most potent compound tested with 99.3% inhibited at a lefamulin concentration antibiotic for IV and oral use in humans and it specifically inhibits bacterial protein synthesis. LEF is currently in Azithromycin Ceftaroline of ≤0.25 mg/L (MIC50/90 values of 0.06/0.12 mg/L). Phase 3 trials for the treatment of community-acquired bacterial pneumonia (CABP). This study investigated the 500 in vitro activity of LEF and comparators against SA strains collected from patients hospitalized with pneumonia in Levofloxacin . The lefamulin activity was not affected by resistance to other antibiotics tested, including macrolides, 2015. Vancomycin tetracyclines, fluoroquinolones, or ß-lactam antibiotics or the nosocomial status of isolates. Number of isolates 0 1,273 unique SA isolates were collected from hospitalized patients with pneumonia worldwide in 28 . Methods: ≤0.03 0.06 0.12 0.25 0.5 1 2 4 >4 31.6% of isolates were MRSA, of which n=139 community-acquired (CA-MRSA) and n=152 were countries (33 sites) in 2015 as part of the SENTRY surveillance program. Isolates included 401 hospital-acquired nosocomial (HA-MRSA). MIC [mg/L] (HA) SA (259 from ICU, 152 from ventilator associated pneumonia, [VAP]). Susceptibility testing was conducted . Lefamulin MIC distributions were similar between subsets, including MSSA vs. MRSA, community- using the CLSI broth microdilution method and susceptibility was interpreted per CLSI 2017 breakpoint criteria. VAP vs. Non-VAP B MRSA vs. MSSA CA-MRSA vs. HA-MRSA ICU vs. Non-ICU acquired vs. nosocomial isolates, ICU vs. non-ICU and VAP vs. non-VAP (Figure 2B). Results: LEF was the most potent compound tested, with 99.7% of all SA isolates being inhibited at a 800 MSSA 200 CA-MRSA 800 S. aureus, 400 S. aureus, . MSSA and MRSA showed lefamulin MIC of 0.06/0.12 mg/L. concentration of ≤0.25 mg/L (MIC values of 0.06/0.12 mg/L) and irrespective of the collection source non-ICU non-VAP 50/90 50/90 600 HA MRSA MRSA 600 S. aureus, (ICU/non-ICU, VAP/non-VAP). 31.6% of isolates (n=402) were MRSA of which 99.3% were inhibited at a LEF S. aureus, . Both CA-SA (n=528; MSSA and MRSA) and HA-SA (n=401) displayed a lefamulin MIC50/90 of VAP 400 ICU 200 concentration of ≤0.25 µg/mL (MIC50/90, 0.06/0.12 mg/L). Susceptibility rates for all SA isolates were >90% for 100 400 0.06/0.12 mg/L MIC50/90. ceftaroline, vancomycin, linezolid and doxycycline. Susceptibility to azithromycin, levofloxacin and clindamycin 200 200 . S. aureus isolates were largely susceptible to doxycycline (97.6%), ceftaroline (93.3%), linezolid was limited, particularly among MRSA (see Table 1). Numberof isolates 0 0 0 0 (99.9%) and vancomycin (100%). ≤0.03 0.06 0.12 0.25 0.5 ≤0.03 0.06 0.12 0.25 0.5 ≤0.03 0.06 0.12 0.25 0.5 ≤0.03 0.06 0.12 0.25 0.5 Conclusion: SA strains collected from patients hospitalized with pneumonia including HAP and VAP were highly . Susceptibility to macrolides, fluoroquinolones and lincosamides was significantly reduced, susceptible to LEF regardless of the resistance phenotype to the other antibiotics tested. Due to its potent MIC [mg/L] MIC [mg/L] MIC [mg/L] MIC [mg/L] particularly among MRSA. activity against resistant SA and the most prevalent typical and atypical respiratory pathogens, as well as the Figure 2. MIC distributions of lefamulin and comparators (A) and lefamulin MIC distribution for . 79.9% of MRSA and 23.9% of MSSA were resistant to azithromycin. availability of IV and oral formulations, LEF has the potential to play a role in the empiric treatment of CABP and various S. aureus subsets (B) supports evaluation in HAP and VAP caused by SA. 77.1% of MRSA and 5.5% of MSSA were resistant to levofloxacin. Table 2. In vitro activity of lefamulin and comparators [mg/L] Table 1. In vitro activity of lefamulin and comparators [mg/L] . 43.0% of MRSA and 3.4% of MSSA were resistant to clindamycin. Organism (n) MIC MIC MIC Range [mg/L] % S a % I a % R a S. aureus, total MSSA MRSA 50 90 99 S. aureus (1,273) (n=1273) (n=871) (n=402) Compound Lefamulin 0.06 0.12 0.12 ≤0.03 - >1 b - - - CONCLUSIONS MIC MIC % S % R % S % R 50 90 Azithromycin 0.5 >4 >4 ≤0.03 - >4 56.6 1.8 41.6 . Lefamulin 0.06 0.12 - - - - Ceftaroline 0.25 1 2 ≤0.06 - 4 93.3 6.6 0.1 Lefamulin displayed potent in vitro activity against this contemporary collection of Azithromycin 0.5 >4 73.9 23.9 19.2 79.9 Clindamycin ≤0.25 >2 >2 ≤0.25 - >2 83.9 0.2 15.9 S. aureus isolates collected from hospitalized patients with pneumonia. Ceftaroline 0.25 1 100.0 0.0 78.9 0.2 Doxycycline ≤0.06 0.25 8 ≤0.06 - >8 97.6 2.2 0.2 . Lefamulin was the most active compound against MRSA and MSSA, including both, Clindamycin ≤0.25 >2 100.0 0.0 57.0 43.0 Erythromycin 0.25 >8 >8 ≤0.06 - >8 56.2 5.1 38.6 community-acquired and nosocomial isolates, irrespective of the resistance phenotype to Doxycycline ≤0.06 0.25 99.4 0.1 93.8 0.2 Levofloxacin 0.25 >4 >4 ≤0.03 - >4 71.2 0.6 28.1 other antibiotic classes including macrolides, fluoroquinolones, tetracyclines or ß-lactam Levofloxacin 0.25 >4 93.8 5.5 22.4 77.1 Linezolid 1 1 2 0.25 - 8 99.9 - 0.1 Oxacillin 0.5 >2 100.0 0.0 0.0 100.0 Oxacillin 0.5 >2 >2 ≤0.25 - >2 68.4 - 31.6 antibiotics. Linezolid 1 2 99.9 0.1 100.0 0.0 Figure 1. Lefamulin Vancomycin 0.5 1 1 ≤0.12 - 2 100.0 0.0 0.0 . These data support the development of lefamulin for infections caused by S. aureus, including Vancomycin 0.5 1 100.0 0.0 100.0 0.0 MRSA (402) CAP, HAP and ABSSSI. Lefamulin 0.06 0.12 0.25 ≤0.03 - >1 INTRODUCTION Azithromycin >4 >4 >4 0.06 - >4 19.2 1.0 79.9 Lefamulin is the first representative of pleuromutilin class in clinical development for systemic Ceftaroline 1 2 2 0.25 - 4 78.9 20.9 0.2 REFERENCES administration. Pleuromutilins inhibit bacterial protein synthesis of Gram-positive and Gram-negative Clindamycin ≤0.25 >2 >2 ≤0.25 - >2 57.0 0.0 43.0 (1) Jain S., et al. NEJM 373, 415-27 (2015) 3,4 Doxycycline ≤0.06 4 8 ≤0.06 - >8 93.8 6.0 0.2 (2) http://ecdc.europa.eu/en/healthtopics/Health care-associated_infections/guidance-infection-preventioncontrol/Pages/ organisms, as well as atypical respiratory pathogens. Lefamulin effectively and selectively inhibits guidance-prevention-control-infections-MRSA.aspx Erythromycin >8 >8 >8 ≤0.06 - >8 18.9 4.7 76.4 bacterial translation by binding to the peptidyl transferase center (PTC) via four H-bonds and other (3) Paukner, et al. AAC 57(9), 4489-4495 (2013) interactions at the A- and P-sites, resulting in an “induced fit.”5,6 Phase 1 and 2 trials have demonstrated Levofloxacin >4 >4 >4 0.06 - >4 22.4 0.5 77.1 (4) Waites, K. B., et al. AAC 61(2)(2017) that IV and oral administration of lefamulin are well tolerated. Furthermore, lefamulin (100 mg or Linezolid 1 1 2 0.25 - 2 100.0 - 0.0 (5) Eyal, Z., et al., Sci Rep 6, 39004 (2016) 150 mg IV q12 hours) showed similar efficacy to IV vancomycin in a clinical Phase 2 trial in patients with Oxacillin >2 >2 >2 >2 - >2 0.0 - 100.0 (6) Paukner, S. and Riedl, R. Cold Spring Harbor Laboratory Perspectives, Antibiotics and Antibiotic Resistance (2016) acute bacterial skin and skin structure infections (ABSSSI).7 Currently lefamulin is in late stage Vancomycin 0.5 1 1 ≤0.12 - 2 100.0 0.0 0.0 (7) Prince, W. T, et al. AAC 57(5), 2087-2094 (2013) a b (8) CLSI, M100(2017) development for the treatment of community-acquired bacterial pneumonia (CABP). Criteria as published by CLSI [2017]; Two of 1,273 isolates showed a lefamulin MIC of >1 mg/L. ID Week 2017, October 4-8, San Diego, CA, USA.
Load more

Recommended publications
  • Unsafe €Œcrossover-Use― of Chloramphenicol in Uganda
    The Journal of Antibiotics (2021) 74:417–420 https://doi.org/10.1038/s41429-021-00416-3 BRIEF COMMUNICATION Unsafe “crossover-use” of chloramphenicol in Uganda: importance of a One Health approach in antimicrobial resistance policy and regulatory action 1,2 1,2 3 1 1 Kayley D. McCubbin ● John W. Ramatowski ● Esther Buregyeya ● Eleanor Hutchinson ● Harparkash Kaur ● 3 2 1 Anthony K. Mbonye ● Ana L. P. Mateus ● Sian E. Clarke Received: 22 December 2020 / Revised: 2 February 2021 / Accepted: 16 February 2021 / Published online: 19 March 2021 © The Author(s) 2021. This article is published with open access Abstract Since the introduction of antibiotics into mainstream health care, resistance to these drugs has become a widespread issue that continues to increase worldwide. Policy decisions to mitigate the development of antimicrobial resistance are hampered by the current lack of surveillance data on antibiotic product availability and use in low-income countries. This study collected data on the antibiotics stocked in human (42) and veterinary (21) drug shops in five sub-counties in Luwero district of Uganda. Focus group discussions with drug shop vendors were also employed to explore antibiotic use practices in the 1234567890();,: 1234567890();,: community. Focus group participants reported that farmers used human-intended antibiotics for their livestock, and community members obtain animal-intended antibiotics for their own personal human use. Specifically, chloramphenicol products licensed for human use were being administered to Ugandan poultry. Human consumption of chloramphenicol residues through local animal products represents a serious public health concern. By limiting the health sector scope of antimicrobial resistance research to either human or animal antibiotic use, results can falsely inform policy and intervention strategies.
    [Show full text]
  • 2020 Antibiotic Reference Guide Trade to Generic
    2020 ANTIBIOTIC REFERENCE GUIDE TRADE TO GENERIC Listing Alphabetically by Trade Name1 Indications2 Route of Administration Trade Names Manufacturer Generic Name Abbreviations* Gram + Gram - PO IM IV Topical Aktob Akorn Tobramycin To, TO, NN, TM, TOB • • Amikin Apothecon Amikacin Ak, AK, AN, AMI, AMK • • • Amoxil GlaxoSmithKline Amoxicillin AMX, Amx, AMOX, AC • • • Ancef GlaxoSmithKline Cefazolin Cfz, CFZ, CZ, FAZ, KZ • • • • Arestin Orapharma Minocycline Min, MIN, MI, MN, MNO, MC, MH • • • Atridox Tolmar Doxycycline Dox, DOX, DC, DOXY • • • Augmentin GlaxoSmithKline Amoxicillin-clavulanic acid AMC, Amc, A/C, AUG, Aug, XL, AML • • • Avelox Bayer Moxifloxacin Mox, MXF • • • Avycaz Allergan Ceftazidime-avibactam CZA • • Azactam Bristol-Myers Squibb Aztreonam Azt, AZT, ATM, AT, AZM • • • Bactocill GlaxoSmithKline Oxacillin Ox, OX, OXS, OXA • • Bactrim Mutual Trimethoprim-sulfamethoxaxole T/S, SXT, SxT, TS, COT • • • Bactroban GlaxoSmithKline Mupirocin MUP, MOP, MU • • Baxdela Melinta Delafloxacin DFX • • • • Biaxin Abbvie Inc. Clarithromycin Cla, CLA, CLR, CLM, CH • • • Cedax Shionogi Ceftibuten CTB, TIB, CB • • • Cefaclor Multiple companies Cefaclor CCL, CEC, Cfr, FAC, CF • • • Cefizox Astellas Ceftizoxime Cz, ZOX, CZX, CZ, CTZ, TIZ • • • Cefobid Pfizer Cefoperazone Cfp, CFP, CPZ, PER, FOP, CP • • • Cefotan AstraZeneca Cefotetan Ctn, CTN, CTT, CTE, TANS, CN • • • • Ceftin GlaxoSmithKline Cefuroxime Crm, CXM, CFX, ROX, FUR, XM • • Cefzil Bristol-Myers Squibb Cefprozil CPZ, CPR, FP • • • Centany J&J Mupirocin MUP, MOP, MU • • Chloromycetin
    [Show full text]
  • Antibiotics Currently in Clinical Development
    A data table from Feb 2018 Antibiotics Currently in Global Clinical Development Note: This data visualization was updated in December 2017 with new data. As of September 2017, approximately 48 new antibiotics1 with the potential to treat serious bacterial infections are in clinical development. The success rate for clinical drug development is low; historical data show that, generally, only 1 in 5 infectious disease products that enter human testing (phase 1 clinical trials) will be approved for patients.* Below is a snapshot of the current antibiotic pipeline, based on publicly available information and informed by external experts. It will be updated periodically, as products advance or are known to drop out of development. Because this list is updated periodically, endnote numbers may not be sequential. In September 2017, the antibiotics pipeline was expanded to include products in development globally. Please contact [email protected] with additions or updates. Expected activity Expected activity against CDC Development against resistant Drug name Company Drug class Target urgent or WHO Potential indication(s)?5 phase2 Gram-negative critical threat ESKAPE pathogens?3 pathogen?4 Approved for: Acute bacterial skin and skin structure infections; other potential Baxdela Approved June 19, Melinta Bacterial type II Fluoroquinolone Possibly No indications: community-acquired bacterial (delafloxacin) 2017 (U.S. FDA) Therapeutics Inc. topoisomerase pneumonia and complicated urinary tract infections6 Approved for: Complicated urinary Rempex tract infections including pyelonephritis; Vabomere Pharmaceuticals β-lactam (carbapenem) other potential indications: complicated Approved Aug. 30, (Meropenem + Inc. (wholly owned + β-lactamase inhibitor PBP; β-lactamase Yes Yes (CRE) intra-abdominal infections, hospital- 2017 (U.S.
    [Show full text]
  • Lefamulin. Comment On: “Novel Antibiotics for Multidrug-Resistant Gram-Positive Microorganisms
    microorganisms Comment Lefamulin. Comment on: “Novel Antibiotics for Multidrug-Resistant Gram-Positive Microorganisms. Microorganisms, 2019, 7, 270” 1,2, 1 1, 1, Despoina Koulenti * , Elena Xu , Isaac Yin Sum Mok y , Andrew Song y, 3, 2, 1,4,5, Drosos E. Karageorgopoulos y , Apostolos Armaganidis y, Jeffrey Lipman z and 3, Sotirios Tsiodras z 1 UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072, Australia; [email protected] (E.X.); [email protected] (I.Y.S.M.); [email protected] (A.S.); [email protected] (J.L.) 2 2nd Critical Care Department, Attikon University Hospital, 12462 Athens, Greece; [email protected] 3 4th Department of Internal Medicine, Attikon University Hospital, 12462 Athens, Greece; [email protected] (D.E.K.); [email protected] (S.T.) 4 Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane 4029, Australia 5 Anesthesiology and Critical Care, Centre Hospitalier Universitaire De Nîmes (CHU), University of Montpellier, 30029 Nîmes, France * Correspondence: [email protected] Equal contribution-both 3rd authors. y They are joint senior authors. z Received: 16 September 2019; Accepted: 19 September 2019; Published: 24 September 2019 Abstract: On 18 August 2019, an article was published in Microorganisms presenting novel, approved anti-Gram-positive antibiotics. On 19 August 2019, the U.S. Food and Drug Administration announced the approval of lefamulin, a representative of a new class of antibiotics, the pleuromutilins, for the treatment of adult community-acquired bacterial pneumonia. We present a brief description of lefamulin.
    [Show full text]
  • In Vitro Activity of Lefamulin Against a Global Collection of Bacterial Pathogens Commonly Causing Community-Acquired
    In Vitro Activity of Lefamulin against a Global Collection of Bacterial Pathogens Commonly Causing Nabriva Therapeutics 1220 Community-Acquired Bacterial Pneumonia (CABP) - SENTRY 2015 www.nabriva.com Lefamulin … [email protected] Paukner, Susanne 1; Sader, Helio S. 2; Streit, Jennifer M. 2; Flamm, Robert K. 2; Gelone, Steven P. 3 1 Nabriva Therapeutics, Vienna, Austria; 2 JMI Laboratories, North Liberty, IA, USA; 3 Nabriva Therapeutics, King of Prussia, PA, USA ABSTRACT INTRODUCTION RESULTS RESULTS continued Background: CABP is the number one reason for death by infectious diseases Community-acquired bacterial pneumonia (CABP) is a major cause of adult and . Lefamulin displayed potent antibacterial activity against this global . Lefamulin was one of the most active compounds against S. pneumoniae worldwide and emerging resistance complicates its treatment. Lefamulin is the first child mortality globally with 3.2 million deaths in 2015 and an estimate of 3.5 collection of contemporary pathogens collected from patients with (MIC50/90 of 0.06/0.12 mg/L) with 99.9% of isolates inhibited at a semi-synthetic pleuromutilin antibiotic for IV and oral use in humans. It is currently million in 2030.1 The aetiology of CABP includes Streptococcus pneumoniae, predominantly respiratory tract infections (Table 3). lefamulin concentration of 0.5 mg/L. in Phase 3 trials for the treatment of CABP in adults. Lefamulin effectively and Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Haemophilus 1,2 . S. pneumoniae isolates were largely susceptible to ceftaroline (99.9%), selectively inhibits bacterial translation by binding to the peptidyl transferase influenzae as significant aetiological agents. Increasing resistance rates to Table 3.
    [Show full text]
  • In Vitro Activity of Lefamulin Against a Collection of Respiratory Pathogens from Pediatric Patients in US
    In Vitro Activity of Lefamulin against a Collection of Respiratory Pathogens from Nabriva Therapeutics AG FRIDAY - 24 Pediatric PatientsLefamulin In US (SENTRY … Surveillance 2015) Vienna, Austria 1 2 2 3 2 www.nabriva.com Paukner, Susanne ; Flamm, Robert K ; S.J. Ryan Arends ; Gelone, Steven P. ; Sader, Helio S. [email protected] 1 Nabriva Therapeutics, Vienna, Austria; 2 JMI Laboratories, North Liberty, IA, USA; 3 Nabriva Therapeutics, King of Prussia, PA, USA ABSTRACT (amended) METHODS RESULTS Background: Lefamulin is the first semi-synthetic pleuromutilin antibiotic for IV and As part of the SENTRY surveillance 776 unique bacterial isolates were . Lefamulin demonstrated potent activity against this contemporary . Lefamulin displayed potent antibacterial activity with 100% of all oral use in humans and is currently in Phase 3 trials for the treatment of CABP in collected from pediatric patients (≤17 years old) in the US in 2015. collection of bacterial isolates collected from pediatric patients in 2015. S. pneumoniae inhibited at concentrations of ≤0.25 mg/L and 100% of adults. Lefamulin effectively and selectively inhibits bacterial translation by binding Susceptibility testing was conducted using the CLSI broth microdilution . H. influenzae isolates at ≤2 mg/L (Table 1, Figure 2). to the A- and P-site of the peptidyl transferase center (PTC) via an induced fit MIC distributions of lefamulin for isolates collected from pediatric and method and susceptibility was calculated using CLSI 2017 breakpoints.7 QC mechanism whereby nucleotides in the PTC shift and tighten the binding pocket adult patients are shown in Figure 1. MIC50/90 and summarized in Table 1.
    [Show full text]
  • Lefamulin the Potential for 1 Antibiotic Rather Than 2 in CABP March 13, 2018
    Lefamulin The potential for 1 antibiotic rather than 2 in CABP March 13, 2018 Prof. Mark H. Wilcox Professor of Medical Microbiology Leeds Teaching Hospitals & University of Leeds Confidential Disclosures Mark H. Wilcox has received Consulting fees from Abbott Laboratories, Actelion, Antabio, AiCuris, Astellas, Astra-Zeneca, Bayer, Biomèrieux, Cambimune, Cerexa, Da Volterra, The European Tissue Symposium, Ferring, The Medicines Company, MedImmune, Menarini, Merck, Meridian, Motif Biosciences, Nabriva, Paratek, Pfizer, Qiagen, Roche, Surface Skins, Sanofi-Pasteur, Seres, Summit, Synthetic Biologics, and Valneva Lecture fees from Abbott, Alere, Allergan, Astellas, Astra-Zeneca, Merck, Pfizer, Roche, and Seres Grant support from Abbott, Actelion, Astellas, Biomèrieux, Cubist, Da Volterra, Merck, MicroPharm, Morphochem AG, Sanofi-Pasteur, Seres, Spero, Summit, and The European Tissue Symposium Confidential Pleuromutilin Antibacterial Agents • Pleuromutilin antibiotics inhibit translation and are O OH R O 14 semisynthetic derivatives of the naturally occurring tricyclic H diterpenoid pleuromutilin isolated from an edible mushroom – Veterinary use: tiamulin and valnemulin (oral treatment of dysentery O Pleuromutilin R = OH and respiratory infections in swine and poultry) Pleurotus mutilus (Clitopilus – Human use: retapamulin (topical treatment of uSSSTI caused by scyphoides) MSSA or Streptococcus spp) Source: James Lindsey's Ecology of Commanster Site, 2006 • Lefamulin was discovered by Nabriva and is the first systemic CH2 pleuromutilin for
    [Show full text]
  • Concept Paper
    Concept Paper: Potential Approach for Ranking of Antimicrobial Drugs According to Their Importance in Human Medicine: A Risk Management Tool for Antimicrobial New Animal Drugs Introduction This concept paper discusses a potential approach to considering the human medical importance of antimicrobial drugs when assessing and managing antimicrobial resistance risks associated with the use of antimicrobial drugs in animals. In 2003, FDA established a list ranking antimicrobial drugs according to their relative importance in human medicine primarily for the purpose of supporting a qualitative risk assessment process outlined in agency guidance. It was envisioned by the Agency at the time the current medical importance rankings list was published that it would periodically reassess the rankings to align with contemporary science and current human clinical practices. To that end, this paper describes a potential revised process for ranking antimicrobial drugs according to their relative importance in human medicine, potential revised criteria to determine the medical importance rankings, and the list of antimicrobial drug medical importance rankings that would result if those criteria were to be used. Disclaimer: This concept paper is for discussion purposes only. The intent of this concept paper is to obtain public comment and early input on a potential approach to consider the human medical importance of antimicrobial drugs when assessing and managing antimicrobial resistance risks associated with the use of antimicrobial drugs in animals. This concept paper does not contain recommendations and does not constitute draft or final guidance by the Food and Drug Administration. It should not be used for any purpose other than to facilitate public comment.
    [Show full text]
  • This Electronic Thesis Or Dissertation Has Been Downloaded from Explore Bristol Research
    This electronic thesis or dissertation has been downloaded from Explore Bristol Research, http://research-information.bristol.ac.uk Author: Sangmalee, Suphattra Title: Attempts to enhance production of pleuromutilin via heterologous expression of the pleuromutilin biosynthesis gene cluster in various host systems General rights Access to the thesis is subject to the Creative Commons Attribution - NonCommercial-No Derivatives 4.0 International Public License. A copy of this may be found at https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode This license sets out your rights and the restrictions that apply to your access to the thesis so it is important you read this before proceeding. Take down policy Some pages of this thesis may have been removed for copyright restrictions prior to having it been deposited in Explore Bristol Research. However, if you have discovered material within the thesis that you consider to be unlawful e.g. breaches of copyright (either yours or that of a third party) or any other law, including but not limited to those relating to patent, trademark, confidentiality, data protection, obscenity, defamation, libel, then please contact [email protected] and include the following information in your message: •Your contact details •Bibliographic details for the item, including a URL •An outline nature of the complaint Your claim will be investigated and, where appropriate, the item in question will be removed from public view as soon as possible. Attempts to enhance production of pleuromutilin
    [Show full text]
  • Gram Positive Cocci (GPC) Gram Neg (Rods = GNR) Anaerobes
    Gram Positive Cocci (GPC) Gram Neg (rods = GNR) Anaerobes Atypicals Classification Antibiotic Cluster Streptococcus Entero- Resp Enteric Non- Bacteroides, Mycoplasma = Staph β↓ & α-hemolytic↓ coccus (cocci) GI flora enteric Clostridium Legionella Beta-Lactams General Spectrum MSSA Group pneumo, faecalis H. flu, E. coli, Pseud- (non-dfficile) Chlamydia Penicillins of Activity → only A / B Viridans only M. cat Klebsiella omonas Peptostrep. (pneumonia) Natural Penicillin G IV/ PenVK PO +/- ++ + + 0 0 0 + 0 Anti- Oxacillin/Nafcillin IV, ++ ++ + 0 0 0 0 0 0 Staphylococcal Dicloxacillin PO Aminopenicillins Amp/Amoxicillin IV/PO 0 ++ + ++ +R +/- 0 + 0 Anti-Pseudomonal Piperacillin/Ticarcillin IV 0 + + + + + ++R + 0 Beta-Lactamase Clavulanate IV/PO, sulbactam Increase Inc by Increase Increase Inhibitor added tazobactam, vaborbactam IV by + + by + by + Cephalosporins Cefazolin IV/ ++ ++ +/- 0 +/- + 0 0 0 1st Generation Cephalexin PO 2nd Generation Cefuroxime IV/PO + ++ + 0 + + 0 +/- 0 Cephamycins Cefoxitin/Cefotetan IV 0 + 0 0 + + 0 + 0 3rd Generation Ceftriaxone/Cefotaxime IV + ++ ++ 0 ++ ++R 0 +/- 0 (PO in between 2nd Ceftazidime IV (+ Avibactam 0 + 0 0 ++ ++R ++R 0 0 and 3rd gen) for Carb-Resistant Enterics) 4th Generation Cefepime IV + ++ ++ 0 ++ ++ ++R 0 0 Novel Ceftolozane-tazo/Cefiderocol 0 + + 0 ++ ++ ++ +/- 0 Carbapenems Imipenem, Meropenem IV + + + +/- ++ ++ ++R ++ 0 (+rele/vaborbactam for CRE) Ertapenem IV + ++ ++ 0 ++ ++ 0 ++ 0 Monobactam Aztreonam IV 0 0 0 0 ++ ++R + 0 0 Non β-Lactams Includes MRSA Both sp. Aminoglycosides Gentamicin,
    [Show full text]
  • In Vitro Activity of Lefamulin Against Contemporary Staphylococcus Aureus Isolates from Patients in Europe (SENTRY 2016)
    P1823 In vitro activity of lefamulin against contemporary Staphylococcus aureus isolates from patients in Europe (SENTRY 2016) Susanne Paukner*1, Robert Flamm2, Rodrigo E. Mendes2, Steve Gelone3, Helio S. Sader2 1Nabriva Therapeutics GmbH, Vienna, Austria, 2JMI Laboratories, North Liberty, United States, 3Nabriva Therapeutics Inc., King of Prussia, United States Background: Lefamulin is the first semi-synthetic pleuromutilin antibiotic for IV and oral treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI). Lefamulin specifically inhibits bacterial protein translation by binding to the peptidyl transferase center (“induced fit”). Lefamulin is highly active in the lung in vivo and has recently completed a Phase 3 clinical trial for the treatment of CABP in adults showing non-inferiority to moxifloxacin (+/-linezolid). Staphylococcus aureus is a well-recognized cause of pneumonia, ABSSSI, and bloodstream infections (BSI), and management can be challenging due to high antibacterial resistance rates. This study investigated the activity of lefamulin and comparators against contemporary S. aureus isolates. Materials/methods: 550 unique S. aureus isolates were collected from hospitalised patients with BSI (50.0%), ABSSSI (30.0%), and pneumonia (20.0%) in 19 European countries (37 sites) during 2016 as part of the SENTRY Surveillance Program. Susceptibility testing was conducted using the CLSI broth microdilution method and susceptibility was interpreted per EUCAST 2017 breakpoint criteria. Results: Lefamulin was one of the most potent compounds tested, with 99.6% of all isolates inhibited at a concentration of ≤0.25 mg/L (MIC50/90 values of 0.06/0.12 mg/L). Susceptibility rates were >90% for clindamycin (MIC50/90, ≤0.25 mg/L/≤0.25 mg/L), doxycycline (MIC50/90, ≤0.06/0.25 mg/L), tigecycline (MIC50/90, ≤0.06/0.12 mg/L), vancomycin (MIC50/90, 0.5/1 mg/L), linezolid (MIC50/90, 1/1 mg/L) and ceftaroline (MIC50/90, 0.25/1 mg/L).
    [Show full text]
  • What's Hot in Infectious Diseases
    What’s Hot in Infectious Diseases - Clinical Science? Stan Deresinski MD FACP FIDSA Clinical Professor of Medicine Stanford University No Disclosures 1884 Pakistan: Salmonella enterica serovar typhi MDR - XDR • November 2016, Hyderabad Pakistan Integrated transposon • Appearance of a H58 haplotype strain encoding amp, chloro, resistant to antibiotics of 5 classes T/S resistance + gyrA • Resulted from acquisition of single mutation chromosomal and plasmid mediated mechanisms by dominant H58 haplotype IncY plasmid* • Plasmid carrying qnrS, blaCTX-M-15 acquired from E. coli blaCTXM-15 • Susceptible only to imipenem, qnrS azithromycin MDR – chloramphenicolR, T/SR, ampicillinR XDR – MDR plus ceftriaxoneR, fluoroquinoloneR mBio. January/February 2018 Volume 9 Issue 1 e00105-18 XDR Typhoid – Pakistan & Beyond • Rapid increase in case numbers with spread to Karachi WHO prequalified use of conjugate vaccine (Typbar-TCV®) – single dose, immunogenic in children >6 months of age • At least 3 travelers returned with infection - one to UK, 2 to US July 11, 2018 “Novartis joins the Big Pharma exodus out of antibiotics, dumping research, cutting 140 and out-licensing programs” https://endpts.com/novartis-joins-the-big-pharma-exodus-out-of-antibiotics-dumping-research-cutting-140-and-out-licensing-programs/ https://gizmodo.com/novartis-becomes-the-latest-pharma-company-to-give-up-o-1827524081 Selected Antibacterials Expected to Be Submitted to the FDA for Approval by Mid-2019 https://cdn2.hubspot.net/hubfs/498900/Jul2018_DrugPriceForecast_Media_FINAL.pdf Cefiderocol • Siderophore cephalosporin • Panel (N=315) of carbapenemase- producing MDR GNR – MIC <4 mcg/ml: • Enterobacteriaeceae – 87.5% • P. aeruginosa - 100% • A. baumanii - 89% • Activity by carbapenemase type: • A – 91.8% B - 74.8% D – 98.0% IDWeek 2017.
    [Show full text]